The conversion of ribonucleotides to deoxyribonucleotides is a critical step in the pathway leading to the formation of DNA. Our primary objective is the rational development of chemotherapeutic agents directed against this reaction. We plan to investigate the role this reaction plays in the regulation of DNA synthesis and cellular replication with particular emphasis on the biochemical events which occur during the initiation of cell division, especially during neoplastic transformation. Upon transformation of a cell from a dormant state to active cell replication large increases in ribonucleotide reductase activity occur. The mechanisms regulating this event will be studied, with particular attention to the identification of and structural features of repressors, as well as factors affecting the half-life of the enzyme and its messenger RNA. The purification and elucidation of the ribonucleotide reductase complex from mammalian tissue will be performed in order to gain additional information about the reaction, determine whether the activities for the reduction of the four ribonucleotide substrates reside with a single enzyme complex, or involve separate enzymes, and to determine the structural features required for a molecule to act as an allosteric effector in this reaction. It is hoped that a better understanding of the various facets of this reaction would lead to exploitable differences that would facilitate design of chemotherapeutic agents directed against this reaction in order to control cellular proliferation and neoplastic disease.